Endothelial monocyte activating polypeptide II (EMAP II) is a polypeptide isolated from methylcholanthrene A-transformed fibrosarcoma cells (Kao et al., J. Biol. Chem. 267:20239-20247, 1992). It is known to inhibit the growth of primary and metastatic tumors and induce apoptosis in proliferating endothelial cells (Schwarz et al., J. Exp. Med. 190:341-353, 1999).
EMAP II is released from the precursor protein p43 during apoptosis. The precursor p43 (pro-EMAP II) protein consists of 312 amino acids and is associated with the multi-tRNA synthetase complex in eukaryotes (Park et al., J. Biol. Chem. 274:16673-166776, 1999). However, it is cleaved to release its C-terminal domain by an activated caspase-7 during apoptosis and to generate EMAP-II (Behrensdorf et al., FEBS Lett. 466:143-147, 2000).
It is known that the EMAP II protein shows sequence similarity with domains present in a variety of different aminoacyl-tRNA synthetases (Quevillon et al., J. Biol. Chem. 272; 32573-32579, 1997) and can bind with tRNA. Also, it is known that 15 peptides at the N-terminal end are involved in the cytokine activity of EMAP II (Kao et al. J. Biol. Chem. 269:9774-9782, 1994).
EMAP II is a mediator of proinflammatory responses that induces the expression of tissue factor, tumor necrosis factor (hereinafter referred to as “TNF”) and interleukin-8 (hereinafter referred to as “IL-8”) in mononuclear phagocyte and polymorphonuclear leucocytes. Also, in a tissue expressing a high level of EMAP II mRNA, macrophages are accumulated. This means that EMAP II is a chemotaxis material directing macrophage to dead cells. It is known that EMAP II acts as a cytokine, and 15 amino acids at the N-terminal domain of EMAP II play a significant role (Quevillon, S. et al., J. Biol. Chem., 272:32573-32579, 1997; Kao, J. et al., J. Biol. Chem., 269:9774-7982, 1994; Kao, J. et al., J. Biol. Chem., 267:20239-20247, 1992; Kao, J. et al., J. Biol. Chem., 269:25106-25119, 1994; Knies, U. E. et al., PNAS USA, 95:12322-12327, 1998). In U.S. Pat. No. 5,641,867 discloses that the N-terminal domain of an EMAP II comprising arginine-isoleucine-glycine-arginine-isoleucine-threonine is an important residue in the cytokine function of the EMAP II. Recently, it was reported that EMAP II repressed the growth of primary and metastatic tumors in proliferating endothelial cells while it did not cause particular side effects in normal cells (Schwarz, M. A. et al., J. Exp. Med., 190:341-353, 1999).
Meanwhile, p43 known as the precursor of EMAP II is known to be expressed extensively. The expression level of p43 protein varies temporally and spatially, especially in a developing mouse. For example, it was shown that the expression of p43 in the lung of 8-16-day-old mice was increased dramatically. In addition, p43 is highly expressed in the microglial cells in the lesions of autoimmune disease such as encephalomyelitis, neuritis and uveitis. The high expression level of p43 in specific developmental stages and tissues suggests that p43 involves inflammation and apoptosis (Tas, M. P. R., and Marray, J. C., Int. J. Biochem. Cell. Biol., 28:837-841, 1996; Schwarz, M. J. et al., Glia, 20:365-372, 1997; Schuesner, H. J. et al., Glia, 20:365-372, 1997; Berger, A. C. et al., J. Immunother., 23:519-527, 2000).
Previously, the present inventor found that monoclonal antibodies specific for EMAP II can be used for the diagnosis and treatment of inflammatory diseases, inhibits the secretion of TNF-α mediating inflammatory responses and is effective for the treatment of Alzheimer's disease (Korean Patent Laid-Open Publication No. 10-2010-0093451).